title: Dopamine receptors modulate cytotoxicity of natural killer cells via cAMP-PKA-CREB signaling pathway.
abstract: Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases.
authors.affiliation: Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Liu
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Cao
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Peng
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Qiu
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D015870:Gene Expression; D007546:Isoquinolines / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019257:Quinpirole / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000235:genetics / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001552:Benzazepines; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D020536:Enzyme Activators; D007546:Isoquinolines; D050637:Receptors, Dopamine D3; C534628:SCH 23390; D013449:Sulfonamides; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; D005576:Colforsin; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide